To date, the use of psychosocial interventions to prevent the major depressive episodes that are commonly precipitated by antiviral treatment for the hepatitis C virus (HCV) has been unexplored. However, cognitive-behavioral treatments for depression (CBT-D) have demonstrated efficacy in a number of different populations, including substance abusers and individuals with medical problems, and have been found to be efficacious in the prevention of depression. The long-term objective of this research program is to improve depression prevention options for methadone maintenance treatment (MMT) patients undergoing interferon (IFN) treatment for hepatitis C by developing and establishing the efficacy of a CBT-D intervention tailored to this population. Furthermore, we seek to advance knowledge of the relationship between depressive symptoms and IFN treatment adherence and illicit drug use relapse. In the present application, we propose to develop a CBT-D intervention tailored to meet the needs of MMT patients undergoing antiviral treatment for hepatitis C. In the first phase of this project (Year 1), we will develop and pilot the intervention with 20 patients. In the second phase of the project (Years 2 and 3), we will conduct a preliminary, randomized trial with 60 MMT patients to examine the efficacy of the CBT-D intervention relative to the relaxation training (RT) control condition that equates for therapist contact time. We expect that, relative to the RT condition, participants randomized to the CBT-D condition will have decreased likelihood of depression-related antiviral treatment failure, will report lower levels of depressive symptoms, will complete more IFN injections, will have lower HCV RNA levels, and will have fewer illicit drug use days. If the efficacy of this intervention can be established in this trial and in subsequent clinical trials, MMT patients who elect to undergo antiviral therapy will have a valuable adjunct or alternative to the use of antidepressants to prevent depression. If found to be efficacious, this intervention will maximize the receipt of IFN treatment by MMT patients, thereby aiding in the prevention of liver failure, hepatocellular carcinoma, and liver-related death among those with HCV.